LOS ANGELES, Jan. 18, 2012-Patients with metastatic melanoma
taking the recently approved drug vemurafenib (marketed as
Zelboraf) responded well to the twice-daily pill, but some of them
developed a different, secondary skin cancer.

Now, researchers at UCLA's Jonsson Comprehensive Cancer Center,
working with investigators from the Institute of Cancer Research in
London, Roche and Plexxikon, have elucidated the mechanism by which
the drug excels at fighting melanoma but also allows for the
development of skin squamous-cell carcinomas.

The very action by which the pill works — blocking the
mutated BRAF protein in melanoma cells that spurs the growth and
spread of tumors — sets off a cellular cascade in other skin
cells (if they have another predisposing cancer mutation) and
ultimately accelerates the secondary skin cancers, said Dr. Antoni
Ribas, co-senior author of the paper and a UCLA professor of
hematology–oncology.

The 18-month study appears in the Jan. 19 edition of the New
England Journal of Medicine.

About 50 percent of patients who get melanoma have the BRAF
mutation and can be treated with vemurafenib, Ribas said. Of those,
approximately one-fourth develop skin squamous-cell carcinomas. In
study subjects, the squamous-cell carcinomas were removed
surgically, and the use of vemurafenib was not discontinued because
of this secondary skin cancer side effect.

"We wondered why it was that we were treating and getting the
melanoma to shrink but another skin cancer was developing," said
Ribas, who studies melanoma at the Jonsson Cancer Center. "We
looked at what was likely making them grow, and we discovered that
the drug was making preexisting cells with an RAS mutation grow
into skin squamous-cell cancers."

The combined research team performed a molecular analysis to
identify the oncogenic mutations in the squamous-cell lesions of
patients treated with vemurafenib. Among 21 tumor samples studied,
13 had RAS mutations. In another set of 14 samples, eight had RAS
mutations, Ribas said.

"Our data indicate that RAS mutations are present in about 60
percent of cases in patients who develop skin squamous-cell cancers
while being treated with vemurafenib," Ribas said. "This RAS
mutation is likely caused by prior skin damage from sun exposure,
and what vemurafenib does is accelerate the appearance of these
skin squamous-cell cancers, as opposed to being the cause of the
mutation that starts these cancers."

Ribas' group found that blocking the non-mutated BRAF in cells
with mutated RAS in an animal model caused them to send signals
around BRAF that induced the growth of the squamous-cell
cancers.

The discovery of the squamous-cell cancer mechanism has led to
strategies to inhibit both the BRAF mutation with vemurafenib and
block the cellular cascade with a different drug — a MEK
inhibitor — before it initiates the secondary skin cancers,
said co-senior author Richard Marais, a professor at the Institute
of Cancer Research in London, who developed the animal model for
the study.

"By understanding the mechanism by which these squamous-cell
cancers develop, we have been able to devise a strategy to prevent
the second tumors without blocking the beneficial effects of the
BRAF drugs," Marais said. "This may allow many more patients to
benefit from these important drugs."

Ribas said that this is one of the very few times that
oncologists understand molecularly why a side effect to cancer
treatment is occurring.

"The side effect in this case is caused by how the drug works in
a different cellular setting," he said. "In one case, it inhibits
cancer growth, and in another, it makes the malignant cells grow
faster."

Studies currently are under way testing BRAF and MEK inhibitors
in combination in patients with metastatic melanoma, Ribas
said.

"Our data provide a molecular mechanism for the clinical
toxicity of a targeted oncogene inhibitor that apparently
contradicts the intended effects," the study states.

The study was supported by Roche; Plexxikon; the Seaver
Institute; the Louise Belley and Richard Schnarr Fund; the Fred L.
Hartley Family Foundation; the Wesley Coyle Memorial Fund; the Ruby
Family Foundation; the Albert Stroberg and Betsy Patterson Fund;
the Jonsson Cancer Center Foundation; and the Caltech–UCLA
Joint Center for Translational Medicine.

UCLA's Jonsson Comprehensive Cancer Center has more than 240
researchers and clinicians engaged in disease research, prevention,
detection, control, treatment and education. One of the nation's
largest comprehensive cancer centers, the Jonsson Center is
dedicated to promoting research and translating basic science into
leading-edge clinical studies. In July 2011, the center was named
among the top 10 cancer centers nationwide by U.S. News & World
Report, a ranking it has held for 11 of the last 12 years.

Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment.